Evaluation of the Tolerability of Switching Patients on Chronic Fulfill

Pain Medicine 2016; 17: 899–907 doi: 10.1093/pm/pnv110

Evaluation of the Tolerability of Switching Patients on Chronic Full l-Opioid Agonist Therapy to Buccal Buprenorphine

Lynn Webster, MD,* Daniel Gruener, MD,† Methods. A randomized, double-blind, double- ‡ ‡ Todd Kirby, PhD, Qinfang Xiang, PhD, dummy, active-controlled, two-period crossover § ¶ Evan Tzanis, and Andrew Finn, PharmD study in adult patients receiving around-the-clock full opioid agonist therapy and confirmed to be opioid dependent by naloxone challenge. Study doses were substituted at the time of the regular *PRA Health Sciences, Salt Lake City, Utah; †St. Louis dose schedule for each patient. The primary end- Clinical Trials, a Subsidiary of Evolution Research point was the proportion of patients with a maxi- Group; ‡Endo Pharmaceuticals Inc., Malvern, mum Clinical Opiate Withdrawal Scale score 13 Pennsylvania; §Former Employee of Endo (moderate withdrawal) or use of rescue medication. Pharmaceuticals Inc.; ¶BioDelivery Sciences Results. 35 subjects on 80 mg morphine sulfate International, Inc, Raleigh, North Carolina, USA equivalent per day were evaluable for opioid with- Correspondence to: Lynn R. Webster, MD, FACPM, drawal. One patient during buccal buprenorphine FASAM, PRA Health Sciences, 3838 South 700 treatment and two during 50% full l-opioid agonist East, Suite 202, Salt Lake City, UT 84106, USA. treatment experienced opioid withdrawal of at least Tel: 801-269-8500; Fax: 919-786-8200; moderate intensity. The mean maximum Clinical E-mail: [email protected]. Opiate Withdrawal Scale scores were similar, and numerically lower on buccal buprenorphine. There Chemical compounds studied in this article: buprenor- were no significant differences in pain ratings phine hydrochloride, CID# 431364. between treatments. The most frequent adverse events with buccal buprenorphine were headache Funding sources: Funding for the research presented (19%), vomiting (13%), nausea, diarrhea, and drug was provided by Endo Pharmaceuticals Inc. withdrawal syndrome (each 9%), and with full l- Disclosure and conflicts of interest: Lynn Webster and opioid agonist were headache (16%), drug with- Daniel Gruener have acted as clinical study investigators drawal syndrome (13%), and nausea (6%). for Endo Pharmaceuticals Inc. Todd Kirby is an Conclusions. Chronic pain patients treated with employee of Endo Pharmaceuticals Inc. and holds stock around-the-clock full l-opioid agonist therapy can be in Endo. Qinfang Xiang is an employee of Endo switched to buccal buprenorphine (a partial l-opioid Pharmaceuticals Inc. and holds stock in Endo. Evan agonist) at approximately 50% of the full l-opioid ago- Tzanis holds stock in Endo. Andrew Finn is a shareholder nist dose without an increased risk of opioid with- and employee of BioDelivery Sciences International, Inc. drawal or loss of pain control. and holds stock options in BioDelivery Sciences. Key Words. Buprenorphine Buccal Film; Opioid; Chronic Pain Abstract

Objective Assess whether patients with chronic Introduction pain receiving 80 to 220 mg oral morphine sulfate equivalent of a full l-opioid agonist could be transi- Buprenorphine is a synthetic opioid classified as a tioned to buccal buprenorphine at approximately Schedule III controlled substance in the United States. 50% of their full dose without inducing opioid with- Buprenorphine is a partial agonist at the l-opioid recep- drawal or sacrificing analgesic efficacy. tor and an antagonist at the j receptor; it is used for

VC 2016 American Academy of Pain Medicine. 899 This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons. org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please contact [email protected] Webster et al. treating acute and chronic moderate to severe pain as eligible for enrollment. In addition, patients were required well as opioid dependence [1–5]. It has properties that to fulfill the following criteria at visits 1, 2, and 3: 6- may provide an improved risk-benefit profile relative to month history of chronic pain (including peripheral neu- other opioids [6,7], including analgesic efficacy with no ropathic pain) requiring 80 but 220 mg MSE per day reported ceiling and an analgesic potency that has been of either morphine sulfate or oxycodone HCl for 28 reported to be 30 to 115 times greater than that of oral days; displaying signs and symptoms of withdrawal (i.e., morphine sulfate [5,7–10]. Buprenorphine has also been Clinical Opiate Withdrawal Scale [COWS] score 5) shown to possess a lower potential for adverse events within 5 minutes following naloxone challenge; stable (AEs) commonly associated with opioid use, such as health, as determined by the principal investigator on constipation [11–13] and respiratory depression the basis of medical history, physical examination, and [4,14,15]. Buprenorphine is an agonist at the opioid screening laboratory results; and, if female, not pregnant receptor-like 1 receptor, the activation of which blocks on the basis of screening serum pregnancy test, and analgesic tolerance and dampens the rewarding effects not lactating. Patients taking opioid medication other of opioids [3–5,16,17], presumably lending to buprenor- than morphine sulfate or oxycodone HCl were not phine’s lower potential for abuse and diversion. enrolled in this trial. Reasons for exclusion were clinically significant pulmonary disease; supine systolic blood A buprenorphine buccal film has been developed using pressure > 180 or < 90 mm Hg or diastolic blood BioErodible MucoAdhesive (BEMAVR ) delivery technology pressure > 105 or < 50 mm Hg at screening; COWS composed of flexible, water-soluble polymeric films that score > 4 before the screening naloxone challenge; adhere to the moist buccal mucosa and erode [18]. aspartate aminotransferase or alanine aminotransferase Buccal buprenorphine (BBUP) doses up to 900 lgtwice > 3 times the upper limits of normal or serum creatinine daily have demonstrated efficacy in controlling chronic low > 1.9 mg/dL at screening; history of alcohol or sub- back pain in both opioid-naive and opioid-experienced stance abuse and/or positive urine drug screen or alco- patients, including those requiring up to 160 mg morphine hol breath test at screening; or at significant risk for sulfate equivalent (MSE) per day, with low incidences of suicidal behavior based on the Columbia-Suicide AEs typically associated with opioid administration [19,20]. Severity Rating Scale (C-SSRS). To be eligible, subjects could not have used monoamine oxidase inhibitors Because buprenorphine has high affinity binding, slow within 14 days of screening or during the study; any receptor dissociation, and low intrinsic activity at the l- medication or nutraceutical or herbal product with cyto- opioid receptor, administration of buprenorphine to chrome P450 (CYP) 3A4 inhibition or induction proper- patients with a significant proportion of l-opioid receptors ties within 30 days of screening; class IA antiarrhythmic occupied by a full l-agonist may result in displacement medications or class III antiarrhythmic medications of the full agonist [21] and induce opioid withdrawal. The within 14 days of screening; or a2-agonist antihyperten- present study was designed to determine whether sives (e.g., clonidine), 5-HT3 antagonists (e.g., ondanse- opioid-experienced patients with chronic pain receiving tron), benzodiazepines, or other medications that were 80 to 220 mg oral MSE daily dose (the dose range com- anticipated to confound detection of signs and symp- monly used in treating opioid-experienced patients with toms of opioid withdrawal. an around-the-clock [ATC] opioid) could be safely converted to buccal buprenorphine HCl without inducing This study was designed and monitored in accordance opioid withdrawal or sacrificing analgesic efficacy. with good clinical practice as required by the major reg- ulatory authorities and the Declaration of Helsinki. The Current recommendations for switching to the transdermal study protocol and protocol amendment were reviewed formulation of buprenorphine available for treating chronic and approved by Copernicus Institutional Review Board, pain call for tapering to the lowest possible dose of a full Durham, NC. Written informed consent was obtained by l-opioid agonist before switching to buprenorphine and the investigator at the screening visit before any assess- titrating to effect [22]. For patients on higher MSE doses, ments were performed. this approach may necessitate a long taper period that may be more difficult to achieve and may require more Study Design clinical oversight than converting to another full agonist at 50% MSE dose. Here we report the results of a double- This was a randomized, double-blind, double-dummy, blind, randomized, controlled trial demonstrating the feasi- active-controlled, two-period crossover study. Patients bility of switching opioid-dependent patients with chronic entered a 7- to 14-day screening period, during which pain directly to BBUP without a taper. they continued to receive their full l-opioid agonist therapy ATC. At visit 1 (screening), patients signed the Methods informed consent and were assessed for protocol eligi- bility, including the naloxone challenge. Participants Eligible patients returned to the clinic 7 to 14 days later Male or female patients 18 to 60 years of age receiving and were admitted for two consecutive nights. Patients ATC therapy with a full l-opioid agonist and confirmed were randomized to one of two treatment sequences, to be opioid dependent by naloxone challenge were AB or BA, where treatment A was two doses of BBUP

900 Full l-Opioid Agonist to Buccal Buprenorphine Switch

Table 1 Original MSE doses and study dose calculations/assignments

Original MSE Original MSE Q12h dose,† mg MSE study BBUP§ study total daily dose,* mg (total daily dose 2) dose‡ Q12h, mg dose Q12h Study group

80 160 40 80 20 40 0.3 mg ¼ 300 mg1 161 220 81 110 41 55 0.45 mg ¼ 450 mg2

BBUP ¼ Buccal buprenorphine; MSE ¼ morphine sulfate equivalent; Q12h ¼ every 12 hours. *If starting with oxycodone, assumes oxycodone-to-morphine ratio of 2:3. †MSE total daily dose divided into 2 Q12h doses. ‡Fifty percent of the total daily dose, administered Q12h. §Assumes buprenorphine-to-morphine analgesic ratio of 100:1. and treatment B was two doses of active full l-opioid Opioid Withdrawal Assessments agonist. A conversion ratio of 100:1 for morphine to buprenorphine dose was used for this study. A sub- The COWS measures 11 opioid withdrawal signs and ject’s original MSE dose was reduced to 50%, and the symptoms in physically dependent patients, including subject was given either 300 or 450 lg of buprenor- pulse rate, sweating, restlessness, pupil size, bone/joint phine. Table 1 outlines the range of original MSE doses, aches, runny nose or tearing, gastrointestinal upset, examples of opioid study dose calculations, and BBUP tremor, yawning, anxiety or irritability, and gooseflesh study dose assignments. skin. Each item is scored from 0 to 4 or 5 for a COWS total score of 0 to 48; the greater the score, the more Study drug was administered as identically appearing severe the withdrawal. A score > 13 is consistent with buccal film containing either buprenorphine or placebo moderate withdrawal. The COWS was administered plus overencapsulated tablets containing morphine sulfate 0.5 hours before each dose of study medication; 0.5, 1, (IR or ER), oxycodone (IR or ER), or matching placebo 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, and 12 hours after the first (double-blind, double-dummy). Patients were administered dose; and 0.5, 1, 1.5, 2, 4, and 12 hours after the sec- the first dose of study drug according to their randomized ond dose of study drug during each period. sequence and monitored in the clinic for signs and symptoms of opioid withdrawal for 12 hours, at which time a Pain Assessments second dose of study drug was administered with an additional 12-hour monitoring period. On day 3, 24 hours During periods 1 and 2, patients rated their “Pain Now” after the first dose of study drug, the patients received intensity 0.5 hours before each dose of study medica- their usual dose of full l-opioid agonist and remained in tion; 0.5, 1, 2, 4, 9, and 12 hours after the first dose; the clinic for approximately 12 hours to ensure that transi- and 0.5, 1, 2, 4, and 12 hours after the second dose tion back to the original analgesic regimen was adequate using an 11-point numerical rating scale (NRS) from 0 for pain control before being discharged to continue out- to 10, where 0 represents “No pain” and 10 represents patient treatment. “Pain as bad as you can imagine.”

Patients returned to the clinic 7 to 14 days later to be admitted for visit 3, where they underwent the same Safety Assessments procedures but received the alternate treatment. Safety evaluations included AEs, laboratory and electro- Buprenorphine dose was based on a 100:1 conversion cardiogram findings, and suicidality as measured by the ratio for morphine to buprenorphine to minimize the risk C-SSRS. of overdosing by underestimating the potency of buprenorphine. BBUP 300-lg and 450-lg doses were Statistical Analysis selected because they represent relative equivalence to 50% of the patients’ MSE. Randomized patients were Safety analyses were performed on all patients who stratified into two groups based on their original ATC received at least one dose of study drug. MSE. MSE Dose Group 1 was composed of patients requiring between 80 and 160 mg MSE per day, and Other analyses were performed using the per-protocol MSE Dose Group 2 was composed of patients requiring population, which included all patients from the safety between 161 and 220 mg MSE per day for 28 days. population who were randomized and did not have major Patients were transitioned only from morphine sulfate or protocol deviations that may have confounded interpreta- oxycodone HCl ATC. Because of slow enrollment in the tion of the COWS, who completed both crossover peri- higher dose group, the study was closed with only the ods, and who provided at least the first 4 hours of COWS 80- to 160-mg MSE group fully enrolled. data for each of the two treatment periods.

901 Webster et al.

The primary endpoint was the proportion of patients The numerical rating scale pain score was analyzed in who experienced opioid withdrawal, defined as a the same manner as the COWS total score; NRS pain maximum COWS score of 13, or required rescue score obtained at 0.5 hours for a treatment was medication because of withdrawal symptoms during the defined as the baseline value for that treatment. 24-hour study period. The rate of withdrawal in each treatment group was estimated using a logistic regres- The number and percentage of patients reporting treat- sion model with repeated measures. It was assumed ment-emergent AEs in each treatment group was tabu- that the withdrawal rate difference between BBUP and lated by treatment group; system organ class; and full l-opioid agonist was 25%. With 32 patients, the preferred term, severity, and relationship to study medi- 95% CI for the percentage withdrawal rate difference cation. All AEs were attributed to one of the study treat- was 5.6% to 44.3%. The maximum COWS score was ments based on the onset time of the events. based on all available data (i.e., the missing values were not imputed). In addition, COWS total scores at each Results time point were summarized using descriptive statistics by treatment for each MSE dose group and overall. Patient Disposition COWS at each time point and maximum COWS total score were summarized using frequency and percent- Disposition of patients is shown in Figure 1. Thirty-nine age based on this rating by treatment group for each patients were randomized, 33 to MSE Dose Group MSE dose group and overall. 1 (80 160 mg) and 6 to MSE Dose Group 2

N=73 Subjects enrolled

n=34 Screened failure (32) Not randomized Subject withdrawal (1) Other (1)

n=39 Subjects randomized

n=33 n=6 MSE dose group 1 MSE dose group 2 (80–160 mg) (161–220 mg)

n=33 n=6 Received Received BBUP ATC opioid and/or (300 µg) and/or BBUP ATC opioid (450 µg)

n=31 n=2* n=5 n=1† Completed Discontinued Completed Discontinued

BBUP ATC opioid BBUP (300 µg) lost to follow-up (1) (450 µg) adverse event (1) lost to follow-up (1)

agonist at visit 2 but did not return for visit 3 to receive buprenorphine. †

Figure 1 Patient disposition. ATC ¼ around-the-clock; BBUP ¼ buccal buprenorphine; MSE ¼ morphine sulfate equivalent.

902 Full l-Opioid Agonist to Buccal Buprenorphine Switch

(161 220 mg). Among these patients, 43.6% took an Of the 33 patients in MSE Dose Group 1 who received IR formulation, 35.9% took an ER formulation, and study medication, 31 (93.9%) completed both periods 20.5% took both types of formulations of full l-opioid of the study. One discontinued BBUP because of an AE agonist during the double-blind treatment period. When and one discontinued full l-opioid agonist due to being used, the IR product or placebos were administered on lost to follow-up. Of the six patients in MSE Dose Group a scheduled basis, not as needed. 2, five (83.3%) completed the study. One patient discontinued after the first treatment period (BBUP) and Table 2 Patient demographics and baseline was lost to follow-up. characteristics (safety population) Demographics MSE dose MSE dose group 1 n ¼ 33 group 2 n ¼ 6 Demographic and baseline characteristics are shown in Table 2. The median age was 43, and the majority of Age, y patients were white (74%) and obese, with a slight Mean 6 SD 41.6 (8.91) 46.0 (10.33) majority female. Median 43 44 Range 26 55 31 60 Withdrawal Analyses Sex, n (%) Male 16 (48.5) 2 (33.3) Thirty-five patients were evaluable for opioid withdrawal; Female 17 (51.5) 4 (66.7) one completer in MSE Dose Group 2 was excluded due Race, n (%) to major protocol violation. Only two patients in MSE White 24 (72.7) 5 (83.3) Dose Group 1 met the definition for opioid withdrawal; Black or African American 9 (27.3) 0 one experienced withdrawal with both BBUP and full American Indian or 0 1 (16.7) l-opioid agonist and the other with full l-opioid agonist Alaska native only. None of the six patients in MSE Dose Group 2 Ethnicity, n (%) met the definition for withdrawal. In MSE Dose Group 1, Hispanic 3 (9.1) 0 the mean of maximum COWS score over the 24-hour Non-Hispanic 30 (90.9) 6 (100) period on BBUP was lower than on full l-opioid agonist (4.6 vs 5.3), but the median maximum COWS scores Weight, kg were identical (4.0). Similarly, in MSE Dose Group 2, the Mean 6 SD 95.0 (23.84) 76.8 (20.11) mean maximum COWS score was lower on BBUP than Median 92.1 78.1 on full l-opioid agonist (5.5 vs 6.3), whereas the median Range 40 142 53 108 COWS score was also slightly lower on BBUP than on Height, cm full l-opioid agonist (6.0 vs 6.5; Table 3). Mean change Mean 6 SD 169.5 (9.05) 168.9 (10.01) from baseline in COWS total score during the 24-hour Median 167.6 166.2 study periods was similar for both treatment groups, as Range 150 185 158 185 depicted in Figure 2. For both study treatments in MSE 2 Body mass index, kg/m Dose Group 1, COWS scores were low during the 4 to Mean 6 SD 33.0 (7.91) 26.9 (7.03) 6 hours postdose and increased slightly by the end of Median 33.7 25.9 each 12-hour dosing period. The percent of subjects in Range 15 50 19 40 each withdrawal severity category across the observa- tion period is shown in Figure 3. The sample size in MSE Dose Group 2 was too small to analyze.

Table 3 Comparison of maximum COWS total score (per-protocol population)

Full l-opioid MSE dose group Statistic BBUP agonist* P value†

Group 1 n 31 31 0.7942 80 160 mg Mean (SD) 4.6 (3.15) 5.3 (4.42) Group 2 n 4 4 0.6155 161 220 mg Mean (SD) 5.5 (1.91) 6.3 (2.50)

BBUP ¼ buccal buprenorphine; CI ¼ confidence interval; COWS ¼ Clinical Opiate Withdrawal Scale; MSE ¼ morphine sulfate equivalent. *Morphine sulfate or oxycodone. †P values were generated using a linear mixed model including sequence, period, and treatment as fixed effects, patient within sequence as random effect, and baseline COWS total score as a covariate.

903 Webster et al.

6.0 MSE dose group 1 (80–160 mg); Treatment: BBUP (n=31) ATC opioid (n=31) 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 0.0 –0.4 –0.8

Change From Baseline in COWS Total Score Total Change From Baseline in COWS –1.2 –1.6 –2.0 0.5 1.5 2.5 3.5 6 9 12 13 14 16 24 Hours Postdose

Figure 2 Mean (6 SE) change from baseline of COWS at selected time points, per-protocol population. ATC ¼ around-the-clock; BBUP ¼ buccal buprenorphine; COWS ¼ Clinical Opiate Withdrawal Scale; MSE ¼ morphine sulfate equivalent.

100% 13–36 (moderate/moderately severe withdrawal) 90% 5–12 (mild withdrawal) 80% 0–4 70% (no withdrawal)

60%

50%

40%

30%

20%

10%

0% ATC ATC ATC ATC ATC ATC BBUP BBUP BBUP BBUP BBUP BBUP Time point 0–3 h 3–6 h 6–9 h 9–12 h12–16 h 16–24 h

Figure 3 Percent of patients with each COWS category at selected time points (80- to 160-mg MSE cohort, per- protocol population). ATC ¼ around-the-clock; BBUP ¼ buccal buprenorphine; COWS ¼ Clinical Opiate Withdrawal Scale; MSE ¼ morphine sulfate equivalent.

Pain Scores mean NRS scores through 9 hours, followed by slight increases from 9 to 12 hours that declined with the sec- Similar results were observed for the NRS pain assess- ond dose. The sample size for MSE Dose Group 2 was ments (Figure 4). There was no change from baseline in too small to analyze.

904 Full l-Opioid Agonist to Buccal Buprenorphine Switch

2.00 MSE dose group 1 (80–160 mg); Treatment: BBUP (n=31) ATC opioid (n=31) 1.75 1.50 1.25 1.00 0.75 0.50 0.25 0.00 –0.25 –0.50 –0.75 –1.00 –1.25 –1.50 –1.75 Change From Baseline in NRS Pain Intensity Score –2.00 0.51 2 4 6 9 12 13 14 16 24 Hours Postdose

Figure 4 Mean (6 SE) change from baseline of NRS pain intensity score at selected time points, per-protocol population. ATC ¼ around-the-clock; BBUP ¼ buccal buprenorphine; MSE ¼ morphine sulfate equivalent; NRS ¼ numerical rating scale.

Safety agonist [21] and precipitate opioid withdrawal. Nevertheless, opioid rotation is an important strategy for Adverse events are summarized in Table 4. In MSE pain management in patients who require chronic opioid Dose Group 1, 18 patients (56.3%) had at least one AE therapy [23]. This randomized, double-blind, active-con- during BBUP treatment, and 13 patients (40.6%) had at trolled study was designed to evaluate the risk of with- least one AE during full l-opioid agonist therapy. drawal syndrome with doses of BBUP administered 8 to Discontinuations due to AEs occurred with one patient 12 hours after the last dose of full l-opioid agonist. Some during treatment with BBUP and three patients during important aspects of the study design were inclusion of ATC treatment. In MSE Dose Group 2, only one patient opioid-dependent patients requiring 80 mg MSE and experienced an AE of drug withdrawal syndrome during documented withdrawal symptoms following a naloxone BBUP treatment. challenge. In addition, this was a crossover study design in which patients received two doses of BBUP at approxi- In MSE Dose Group 1, the percent of patients with AEs mately 50% of their MSE dose and two doses of active considered related to treatment was 31.3% (10 patients) full l-opioid agonist at 50% of their prescribed total daily with BBUP and 21.9% (7 patients) with full l-opioid ago- dose, allowing for direct comparison of withdrawal effects nist. The most frequent AEs with BBUP were headache from the two treatments in the same patients. (19%); vomiting (13%); and nausea, diarrhea, and drug withdrawal syndrome (each 9%). The most frequent AEs For the primary efficacy analysis, opioid withdrawal was with full l-opioid agonist were headache (16%), drug defined as a maximum COWS total score that was at withdrawal syndrome (13%), and nausea (6%). least 13 or the patient requiring rescue medication for withdrawal symptom management. Only two patients No deaths occurred during the study; one patient in MSE experienced withdrawal during one or both study treat- Dose Group 1 experienced serious AEs of chest pain and ments, both in the MSE Dose Group 1 stratum dyspnea when treated with buprenorphine. No clinically (80 160 mg). The mean maximum COWS scores did meaningful trends were noted in laboratory test results, not show any significant difference between full l-opioid vital signs, physical examination findings, or C-SSRS. agonist and BBUP (P ¼ 0.79) Similarly, there was no change from baseline in mean pain NRS scores through Discussion 9 hours postdose. The data did not suggest any difference in opioid withdrawal following BBUP and full Buprenorphine is a partial agonist at the l-opioid receptor l-opioid agonist administered at 50% of the therapeutic agonist and an antagonist at the j receptor, with high dose. Thus, patients can rotate from a full l-opioid ago- affinity binding and slow dissociation from receptors, as nist to BBUP in the 80- to 160-mg MSE dose range well as low intrinsic activity at the l-opioid receptor [21]. It without any greater risk of precipitating withdrawal than is possible that administration of buprenorphine to patients would be expected when switching to another opioid. with a high percentage of l-opioid receptors occupied by Administration of 300- or 450-lg doses of BBUP 8 to afulll-agonist could result in displacement of the full 12 hours after the last dose of full l-opioid agonist was

905 Webster et al.

Table 4 Number (%) of patients with TEAEs—safety population

MSE Dose Group 1 (80 160 mg) MSE Dose Group 2 (161 220 mg) System organ class preferred BBUP Full l- agonist* Overall BBUP Full l-agonist* Overall term, n (%) n ¼ 32 n ¼ 32 n ¼ 33 n ¼ 6 n ¼ 5 n ¼ 6

At least 1 TEAE 18 (56.3) 13 (40.6) 20 (60.6) 1 (16.7) 0 1 (16.7) Gastrointestinal disorders 7 (21.9) 5 (15.6) 10 (30.3) 0 0 0 Nausea 3 (9.4) 2 (6.3) 5 (15.2) 0 0 0 Diarrhea 3 (9.4) 1 (3.1) 4 (12.1) 0 0 0 Vomiting 4 (12.5) 1 (3.1) 4 (12.1) 0 0 0 Abdominal discomfort 0 1 (3.1) 1 (3.0) 0 0 0 General disorders and 4 (12.5) 4 (12.5) 6 (18.2) 1 (16.7) 0 1 (16.7) administration site conditions Drug withdrawal syndrome 3 (9.4) 4 (12.5) 5 (15.2) 1 (16.7) 0 1 (16.7) Chest pain 1 (3.1) 0 1 (3.0) 0 0 0 Investigations 1 (3.1) 0 1 (3.0) 0 0 0 Oxygen saturation decreased 1 (3.1) 0 1 (3.0) 0 0 0 Musculoskeletal and connective 2 (6.3) 0 2 (6.1) 0 0 0 tissue disorders Arthralgia 1 (3.1) 0 1 (3.0) 0 0 0 Back pain 1 (3.1) 0 1 (3.0) 0 0 0 Nervous system disorders 8 (25.0) 5 (15.6) 11 (33.3) 0 0 0 Headache 6 (18.8) 5 (15.6) 9 (27.3) 0 0 0 Dizziness 1 (3.1) 0 1 (3.0) 0 0 0 Somnolence 1 (3.1) 0 1 (3.0) 0 0 0 Respiratory, thoracic, and 1 (3.1) 1 (3.1) 2 (6.1) 0 0 0 mediastinal disorders Dyspnea 1 (3.1) 0 1 (3.0) 0 0 0 Hypoxia 0 1 (3.1) 1 (3.0) 0 0 0

BBUP ¼ buccal buprenorphine; TEAE ¼ treatment-emergent adverse event. *Morphine sulfate or oxycodone. At each level of patient summarization, a patient is counted once if the patient reported one or more events (n). not associated with a higher incidence of serious AEs, Conclusions AEs leading to discontinuation, or treatment-emergent AEs overall compared with the 50% dose of the pre- Chronic pain patients treated with around-the-clock full l- scribed full l-opioid agonist. opioid agonist therapy can be switched to buccal buprenorphine (a partial l-opioid agonist) at approximately 50% One limitation of this study is that the full l-opioid ago- of the full agonist dose without an increased risk of opioid nists used in this study and buprenorphine are different withdrawal or loss of pain control. molecules with different receptor affinities; it cannot be stated unequivocally that the doses were comparable. Acknowledgments As in all opioid conversions, the 50% MSE represents a best estimate. Second, all subjects were converted Funding for the research and editorial support was pro- from morphine or oxycodone, so results may not be vided by Endo Pharmaceuticals Inc. applicable to other opioids. In addition, the prespeci- fied calculation of the odds ratio of buprenorphine to full l-opioid agonist could not be calculated because References of the small number of patients who met the definition 1 Kajiwara M, Aoki K, Ishii K, et al. Agonist and antag- for opioid withdrawal. Furthermore, no conclusions can onist actions of buprenorphine on three types of be drawn from the high-dose cohort because of the opioid receptor in isolated preparations. Jpn J small sample size. Overall, the results suggest that Pharmacol 1986;40:95–101. switching patients to a 50% MSE dose of BBUP is comparable in safety and tolerability to reducing a 2 Leander JD. Buprenorphine is a potent kappa- patient to a 50% MSE dose of their current full l- opioid receptor antagonist in pigeons and mice. Eur opioid agonist therapy. J Pharmacol 1988;151:457–61.

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